Intellectual disability (ID) is a common morbid condition with a wide range of etiologies. The list of monogenic forms of ID has increased rapidly in recent years thanks to the implementation of genomic sequencing techniques. In this study, we describe the phenotypic and genetic findings of 68 families (105 patients) all with novel ID-related variants. In addition to established ID genes, including ones for which we describe unusual mutational mechanism, some of these variants represent the first confirmatory disease-gene links following previous reports (TRAK1, GTF3C3, SPTBN4 and NKX6-2), some of which were based on single families. Furthermore, we describe novel variants in 14 genes that we propose as novel candidates (ANKHD1, ASTN2, ATP13A1, FMO4, MADD, MFSD11, NCKAP1, NFASC, PCDHGA10, PPP1R21, SLC12A2, SLK, STK32C and ZFAT). We highlight MADD and PCDHGA10 as particularly compelling candidates in which we identified biallelic likely deleterious variants in two independent ID families each. We also highlight NCKAP1 as another compelling candidate in a large family with autosomal dominant mild intellectual disability that fully segregates with a heterozygous truncating variant. The candidacy of NCKAP1 is further supported by its biological function, and our demonstration of relevant expression in human brain. Our study expands the locus and allelic heterogeneity of ID and demonstrates the power of positional mapping to reveal unusual mutational mechanisms.

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Encephalitis associated with VGKC Ab occurs in children and presents with status epilepticus and focal epilepsy. These antibodies are not directed against Lgi1 or Caspr2.

Summary Purpose Potentially pathogenic autoantibodies are found increasingly in adults with seizure disorders, including focal seizures and those of unknown cause. In this study, we investigated a cohort of children with new‐onset seizures to see whether there were autoantibodies and the relationship to any specific seizure or epilepsy type. Methods We prospectively recruited 114 children (2 months to 16 years) with new‐onset seizures presenting between September 2009 and November 2011, as well as 65 controls. Patients were clinically assessed and classified according to the new International League Against Epilepsy (ILAE) organization of seizures and epilepsies classification system. Sera were tested for autoantibodies to a range of antigens, blind to the clinical and classification details. Key Findings Eleven (9.7%) of 114 patients were positive for one or more autoantibodies compared to 3 of 65 controls (4.6%, p = ns). Patients had antibodies to the voltage‐gated potassium channel (VGKC) complex (n = 4), contactin‐associated protein‐like 2 (CASPR2) (n = 3), N‐methyl‐d‐aspartate receptors (NMDARs) (n = 2), or VGKC‐complex and NMDAR (n = 2). None had antibodies to glutamic acid decarboxylase, contactin‐2, or to glycine, 2‐amino‐3‐(3‐hydroxy‐5‐methyl‐4‐isoxazolyl) propionic acid (AMPA), or γ‐aminobutyric acid B receptors. Ten of these 11 patients were classified as having epilepsy according to the new ILAE organization of seizures and epilepsy. Although, there were no significant differences in the demographic and clinical features between antibody‐positive and antibody‐negative patients, the classification of “unknown cause” was higher in the antibody positive (7/10; 70%) compared with the antibody negative subjects (23/86; 26.7%; p = 0.0095, Fisher's exact test). Furthermore, four of these seven patients with epilepsy (57.1%) were classified as having predominantly focal seizures compared with 12 of the 86 antibody‐negative patients (13.9%; p = 0.015). Significance Because autoantibodies were more frequent in pediatric patients with new‐onset epilepsy of “unknown cause,” often with focal epilepsy features, this group of children may benefit most from autoantibody screening and consideration of immune therapy.